Department of Cardiac Development and Remodelling, Excellence Cluster Cardio-Pulmonary System, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, Bad Nauheim 61231, Germany.
Cardiovasc Res. 2010 Apr 1;86(1):92-102. doi: 10.1093/cvr/cvp383. Epub 2009 Dec 2.
Although the fundamental role of the E2F transcription factor family in cell proliferation is well established, the specific function of E2F4 is unclear. On the basis of findings from cell culture experiments, E2F4 is generally considered as an inhibitor of cell proliferation. Accumulating evidence suggests, however, that E2F4 acts as an activator of cell proliferation in certain contexts. Here, we have investigated the role of E2F4 during heart development and in proliferating cardiomyocytes.
Nuclear E2F4 expression in cardiomyocytes declined during mouse heart development, which correlates with the loss of proliferative capacity of cardiomyocytes. Re-induction of proliferation in postnatal cardiomyocytes increased nuclear E2F4 expression. E2F4 accumulated in the nucleus at the end of the S phase, remained nuclear during mitosis, and disappeared at the end of cytokinesis. siRNA-mediated inhibition of E2F4 in proliferating postnatal cardiomyocytes resulted in a significant reduction in mitosis, but not in DNA synthesis. Co-staining of E2F4 and Crest revealed that E2F4 co-localizes with kinetochores. Moreover, chromatin immunoprecipitation showed that E2F4 binds to centromeric alpha-satellite DNA during mitosis.
Our data indicate that E2F4 is required for cardiomyocyte proliferation and suggest a function for E2F4 in mitosis.
尽管 E2F 转录因子家族在细胞增殖中的基本作用已得到充分证实，但 E2F4 的具体功能尚不清楚。基于细胞培养实验的发现，E2F4 通常被认为是细胞增殖的抑制剂。然而，越来越多的证据表明，E2F4 在某些情况下作为细胞增殖的激活剂发挥作用。在这里，我们研究了 E2F4 在心脏发育和增殖性心肌细胞中的作用。
在小鼠心脏发育过程中，心肌细胞中的核 E2F4 表达下降，这与心肌细胞增殖能力的丧失相关。在出生后心肌细胞中重新诱导增殖会增加核 E2F4 的表达。E2F4 在 S 期结束时积累在核内，在有丝分裂期间保持在核内，并在胞质分裂结束时消失。在增殖的出生后心肌细胞中用 siRNA 抑制 E2F4 会导致有丝分裂显著减少，但 DNA 合成不受影响。E2F4 和 Crest 的共染色表明 E2F4 与着丝粒共定位。此外，染色质免疫沉淀显示 E2F4 在有丝分裂期间与着丝粒α卫星 DNA 结合。
我们的数据表明 E2F4 是心肌细胞增殖所必需的，并提示 E2F4 在有丝分裂中的作用。
